Treatment of pruritus with vitamin d and analogs thereof

ABSTRACT

A method for treating pruritus comprising topical administration of formulation of vitamin D or an analog of vitamin D is disclosed. The formulation comprises a therapeutically effective, water-based emulsion, water-based suspension or oil-based formulation of vitamin D or analog of vitamin D.

BACKGROUND OF THE INVENTION

[0001] (1) Field of the Invention

[0002] This invention relates generally to the field of treatingpruritus and, more particularly, to the topical treatment of pruritususing vitamin D and analogs thereof.

[0003] (2) Description of the Related Art

[0004] Pruritus is a condition involving localized or general itchingwhich can be mediated by stimulation of sensory nerve endings. Althoughusually occurring in the skin, pruritus can also occur in non-cutaneoussites such as mucous membranes or cornea. A variety of causes for thecondition of pruritus are known including external and exogenous causes,localized skin disorders and systemic diseases.

[0005] The first line of treatment involves diagnosis of the underlyingcondition that causes the pruritus and intervening therapeutically toalleviate that underlying condition. Such therapeutic treatment isappropriate for example in the treatment of psoriasis with UV light orwith topical vitamin D₃ analogs. These treatments are not considered tobe direct treatments of the pruritus and only indirectly relieve theitching. Indeed, some treatment modalities for psoriasis can causeitching (for example, see product insert for the vitamin D analogDovonex®, Westwood-Squibb). At the same time the underlying disease isbeing treated, it might also be desirable to directly treat thepruritus. Furthermore in some conditions involving pruritus, either theunderlying cause for the pruritic condition cannot be determined or itcannot be eliminated. In such cases the direct treatment of the pruriticcondition is required.

[0006] Currently available treatment modalities for pruritus includenonspecific topical agents such as emollients and counterirritants,topical drugs such as steroids, local anesthetics and antihistamines,and physical modalities such as ultraviolet phototherapy and thermalstimulation. Some of these treatments are effective in pruriticconditions of particular etiology, while others may show general butnonspecific benefit.

[0007] Nonspecific topical preparations can act as moisturizing lotionsor creams or as oil-based ointments that are occlusive and serve tosoften dry skin as well as providing a protective covering. These cansometimes contain chemical substances in the preparation which do notcontribute to the nonspecific antipruritic action of the preparation andprovide no antipruritic action themselves.

[0008] Topical formulations containing pharmacologically active agentsare often useful in particular pruritic conditions but may not begenerally useful in all pruritic conditions. For example, topicalcorticosteroids are not indicated for symptomatic treatment unless asteroid responsive disorder is diagnosed. Physical modalities such as UVlight have been particularly effective in a variety of conditionsalthough undesirable side effects can be produced by UV light such as anincreased risk of developing skin cancer as well as undesirablephototoxic reactions (see for example, Marks, J Dermatol Treat1:233-234, 1989) Thus it would be desirable to develop new anti-pruriticagents that are effective in treating pruritus resulting from a widevariety of causes or that are able to alleviate pruritus produced bydifferent causes than those that can be treated by currently availableagents.

[0009] The ability of vitamin D₃ to effectively treat pruritus whenadministered in a topical treatment formulation has not been heretoforeknown. The effectiveness of UVB light therapy in the treatment ofpruritus has been noted to be incidentally related to the production ofvitamin D in the skin (Blachley et al., Am J Kidney Dis 5:237-241,1985). The same wavelengths of between 290 and 310 nm used in UVBtreatment is also able to photolyze provitamin D₃(7-dehydrocholesterol)which then internally isomerizes to form vitamin D₃. Nevertheless nodirect link between vitamin D₃ production in the skin and theantipruritic effectiveness of UVB light treatment has been reported and,in addition, the mechanism of the therapeutic benefit of UVB lightremains unknown.

[0010] Vitamin D₃ is also incidentally present in some formulations thatare indicated to be useful in certain conditions involving itching. Onesuch nonspecific topical preparation was reported In U.S. Pat. No.3,711,602 issued to Herschler. This patent discloses a formulationcontaining lanolin, DMSO, isopropyl myristate, vitamin A and vitamin D ³that is applied topically for the treatment of burns, skin irritation,diaper rash and pruritus. This preparation is nonaqueous and providesocclusion and physical soothing actions. It is believed, however, thatthe vitamin D present in the formulation at a concentration of 7.5 μg/mldoes not directly contribute any anti-pruritic effect. This is becausethe lowest concentration found to have an anti-pruritic effect in anon-aqueous vehicle in the studies reported herein was 521 μg/ml.

[0011] Other preparations that serve as nonspecific, physically soothingformulations also sometimes contain vitamin D such as for example A andD® Ointment for soothing relief of diaper rash or Desitin® also used tosooth diaper rash including preventing the burning, pain and itchproduced by irritants. These preparations, however, provide only aprotective physical barrier to water and irritants and the vitamin Dpresent in these preparations is incapable of producing any directantipruritic action as a result of not being bioavailable from suchformulations.

[0012] Thus, although vitamin D₃ has been incidentally related to sometreatment modalities for pruritus, it has not heretofore been known thatvitamin D₃ can be effectively used in the treatment of pruriticconditions.

SUMMARY OF THE INVENTION

[0013] In accordance with the present invention, it has been discoveredthat vitamin D can be applied topically in certain formulations thatmake the vitamin D bioavailable. Surprisingly, when administered in suchformulations at pruritic sites, the vitamin D becomes therapeuticallyeffective and the pruritus is rapidly and completely relieved.

[0014] Because vitamin D is a fat soluble substance, a water-basedemulsion formulation that is bioavailable and suitable for topicaltreatment can be used. Thus, one formulation for vitamin D that iseffective in-treating pruritus comprises a mixture of water, awater-insoluble organic liquid, a surface active agent, and a vitamin Dor an analog thereof. This formulation is effective when the vitamin Dis present at a concentration as low as 2.5 μg/ml.

[0015] A second formulation that is also effective in treating pruritusis based upon a nonaqueous carrier vehicle for vitamin D. Thisformulation comprises a water-insoluble organic liquid such as petroleumor corn oil and vitamin D. The vitamin D concentration in thisformulation can be as low as 521 μg/ml.

[0016] Another vitamin D formulation effective in treating prurituscomprises a suspension of water and a dispersed phase containing vitaminD or analog thereof. This formulation is effective at concentration of12.5 μg/ml.

[0017] Among the several advantages achieved by the present invention,therefore, may be noted the provision of new treatment for pruritus thatis broadly effective in a variety of pruritic conditions; the provisionof a treatment modality that is safe being neither irritating nor toxic;the provision of a treatment that is inexpensive; and the provision of atreatment that has a low potential for sensitizing the treatment site byvirtue of its being an endogenous or closely related to an endogenoussubstance.

BRIEF DESCRIPTION OF THE DRAWING

[0018] The FIGURE illustrates the concentration-response relationship ofthe antipruritic effect of vitamin D₃ (0.25-5.0 μg/ml) in alleviatingthe itching produced by poison ivy.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The present invention is thus based upon the discovery thatvitamin D can effectively treat pruritic conditions when administeredtopically in a therapeutically effective formulation. By atherapeutically effective formulation it is meant that the activesubstance is bioavailable, that is able to exert a biological activitywhen administered in that formulation. Such formulations effectivelyexhibit the biological activity of vitamin D in diminishing orcompletely alleviating the itching involved in pruritic conditions. Theformulation is also pharmaceutically acceptable for topical application.

[0020] Vitamin D within the scope of this invention is intended toinclude vitamin D₃ or cholecalciferol as well as the several relatedsteroids and their metabolites that are referenced in the art by theterm vitamin D provided such compound show the biological activity ofvitamin D. Thus vitamin D compounds include alfacalcidol, calcifedol,calcitriol, cholecalciferol, dihydrotachysterol, and ergocalciferol(Martindale, The Extra Pharmacopoeia 30th Ed., Martindale, 1993, pp.1058-1059).

[0021] Also included within the scope of this invention and within themeaning of the term vitamin D are analogs of vitamin D. Analogs ofvitamin D are well known in the art and such compounds can havemodifications in the side chain and/or changes in the nuclear part ofthe secosteroid molecule. Vitamin D analogs can contain side chainmodifications involving introduction of unsaturation; transposing,adding, removing or substituting hydroxyl groups; substitutinghydrogens; forming carbocyclic structure; introducing a heteroatom link;inverting stereochemically; removing or adding alkyl groups and changingthe number of links in the side chain. (see Calverly and Jones, inAntitumor Steroids blickenstagg, Ed., Academic Press, Inc., San Diego,1992, 193-270 which is incorporated by reference). All of these compoundare thus included in the term vitamin D so long as they exhibit thebiological activity of antipruritic effectiveness in a bioavailableformulation. Such biologically active vitamin D compounds may not showthe same degree of activity as vitamin D₃, but need only show at leastsome discernable antipruritic effect.

[0022] One embodiment of the present invention is an aqueous-basedemulsion formulation comprising water, a water-insoluble organic liquid,a surface active agent and vitamin D. The surface active agent isbiocompatible and suitable for application by topical formulation. Theformulation also contains a biocompatible water-insoluble organic liquidsuch as an oil or lipid suitable for forming an oil-in-water orwater-in-oil emulsion so that the formulation is a cream, ointment,paste or the like. By biocompatible it is meant that the substanceproduces no untoward biological effects such as local or generalizedtoxic effects or local irritation at the site of topical application.Suitable water-insoluble organic liquids are well known in the art fieldof topically applied cosmetics and therapeutics and include but are notlimited to mineral oil, corn oil or other vegetable oil, petroleum,lanolin, fish oil and the like.

[0023] The use of surface active agents in preparations that aretopically applied is well known particularly in the field of cosmetics(for example see Surfactants in Cosmetics, Rieger, M., Ed., MarcelDekker, Inc., N.Y., 1985 which is incorporated by reference). Thus, anumber of biocompatible surface active agents can be used in the presentinvention including but not limited to (1) anionic surfactants such asmonovalent or polyvalent carboxylate salts, acyl lactylates, alkyl ethercarboxylates, N-Acyl Sarcosinates, N-Acyl Glutamates, fattyacid-polypeptide condensates, sulfuric acid esters including alkylsulfates and ethoxylated alkyl sulfates, ester-linked sulfonates, alphaolefin sulfonates, phosphated ethoxylated alcohols; (2) cationicsurfactants such as monoalkyl quaternary ammonium salts, dialkylquaternary ammonium compounds, amidoamines and aminimides; (3)amphoteric surfactants such as N-substituted alkyl amides, N-alkylbetaines, sulfobetaines, and N-alkyl beta-aminopropionates; and (4)nonionic surfactants such as (a) polyoxyethylene compounds includingethoxylated alcohols, ethoxylated esters and ethoxylated amines; (b)polyoxypropylene compounds such as propoxylated alcohols,ethoxylated/propoxylated block polymers and propoxylated esters; (c)alkanolamines; (d) amine oxides; and (e) fatty acid esters of polyhydricalcohols such as ethylene glycol esters, diethylene glycol esters,propylene glycol esters, glyceryl esters, polyglyceryl fatty acidesters, sorbitan esters, sucrose esters and glucose esters.

[0024] The selection of a particular surface active agent would dependupon a number of factors including but not limited to the particularcausation agent for the pruritic condition and whether topical lesionsaccompany the pruritic condition. The formulations of the presentinvention are useful in treating pruritic conditions on the skin, mucousmembranes or cornea. Selection of a suitable surface active agent canthus be based in part on the site being treated. For example, amphotericor nonionic surface active agents known in the art are selected for usesin and around the eyes to avoid corneal irritation. One skilled in theart can readily select a surface active agent and formulation suitablefor a particular site and pruritic condition as well as for otherfactors.

[0025] In another embodiment of the present invention a water-insolubleformulation is provided comprising a biocompatible, water-insolubleorganic liquid such as a biocompatible oil or lipid suitable as acarrier for the vitamin D. The carrier must be suitable in the sense ofbeing compatible with the vitamin D and any other ingredients and notdeleterious to the patient being treated. Suitable organic liquidsinclude petroleum jelly, corn oil or other vegetable oil, mineral oil,lanolin, fish oil and the like.

[0026] The Vitamin D compounds of the present invention can also beformulated into bioavailable suspensions or dispersions such as, forexample, hydrosols and hydrogels in which a true emulsion is not formed.The formulation is a mixture of two or more substances forming adispersed phase which is finely divided and uniformly distributedthrough a dispersion medium which is usually water. The dispersed phasecan be a solid or an oil phase with stabilizers to form a stabilizedcolloidal system. Suspending or dispersing agents may also be added tothe formulation and can include surface active agents capable ofstabilizing the suspension or dispersion. The preparation of suspensionsand ingredients used in the formation of suspensions are well known inthe art and one skilled in the art can readily prepare such suspension.

[0027] In addition to the above ingredients, the formulations of thisinvention may also include one or more additional auxiliary ingredientssuch as diluents, buffers, or preservatives such as methylhydroxybenzoate and/or anti-oxidants and the like. Such additionalingredients can also be pharmaceutically-acceptable excipients formodifying or maintaining the pH, osmolarity, viscosity, clarity, color,sterility, stability, rate of dissolution, or odor of the formulation.Similarly, the formulation may contain still otherpharmaceutically-acceptable excipients for modifying or maintainingrelease or absorption or penetration of the site by the vitamin Dcompound. Moreover, other therapeutic substances can be incorporatedinto the formulation such as, for example, other antipruritic agents,vitamins, antifungals, antiinflammatory agents, antibiotics, sunscreensand the like.

[0028] The topical formulations described herein can be used in treatingvirtually any pruritic site such as for example on the skin, mucousmembranes or cornea. Such treatments include scalp treatment as inshampoos, conditioners and the like, rectal treatment, eye treatment,treatment of nasal membranes, treatment of the ear canal, etc.

[0029] The formulations in the present invention are intended for use intreating a wide variety of pruritic conditions in humans as well as innon-human mammals, birds, reptiles, amphibians and fish. Conditions thatare intended for treatment by the present invention include but are notlimited to chickenpox, shingles, plant toxins such as poison ivy, insectbites, chronic kidney failure, liver diseases such as primary biliarycirrhosis and alcoholic cirrhosis, malabsorption syndromes such assteatorhea, HIV infection, AIDS related eosinophilic pustularfolliculitus, psoriasis, atopic dermatitis, photosensitivity disorders,lichen planus, polycythemia vera, Grover's disease, glanuloma annulare,lichen nitidus, prurigo nodularis, macular amyloidosis, urticariapigmentosa, aquagenic pruritus, pemphigus vulgarus, lupis vulgaris,healing cuts and burns, senile pruritus, hypereosinophilic syndrome,chronic uticaria, pruritic eye conditions, and stress.

[0030] Preferred embodiments of the invention are illustrated in thefollowing examples. Other embodiments within the scope of the claimsherein will be apparent to one skilled in the art from consideration ofthe specification or practice of the invention as disclosed herein. Itis intended that the specification, together with the examples, beconsidered exemplary only, with the scope and spirit of the inventionbeing indicated by the claims which follow the examples.

EXAMPLE 1

[0031] This example illustrates antipruritic effect of vitamin D₃ inVita Moist Hand and Nail Cream in the alleviating the pruritus ofchickenpox.

[0032] Having becoming ill with chickenpox, I developed severe pruritus.I applied the commercially available skin cream, Vita Moist Hand andNail Cream (Avon, N.Y.) hereinafter referenced as Vita Moist Cream andthe pruritus was completely and immediately alleviated. The effect ofthe cream lasted for several hours and when the itching returned, Ireapplied the cream with the result that the pruritus was againcompletely and immediately alleviated.

[0033] Vita Moist Cream is sold as a skin moisturizer and carries noindication for use in treating pruritus. Upon reviewing the medicalliterature, I learned that UVB light was effective in treating pruriticconditions and that, incidentally, UVB light also produces vitamin D₃, Iconcluded that vitamin D₃ was likely to be the active ingredient in VitaMoist Cream. As commercially available, Vita Moist Cream contains 10μg/ml vitamin D₃ among other ingredients. Ingredients present in VitaMoist Cream are as follows: VITA MOIST CREAM A Purified Water E GlycolStearate E Glycerin E Isopropyl Palmitate E Dimethicone E MyristylMyristate E Peg-40 Stearate E Stearyl Alcohol E Steareth-2 E Mineral OilF Methylparaben F Imidazolidinyl Urea F Triethanolamine F Fragrance FCarbomer-934 .02000 Retinyl Palmitate .02000 Tocopheryl Acetate G CornOil G Hydrolyzed Animal Keratin G Propylene Glycol G SD Alcohol 40-B.00100 Cholecalciferol G Disodium EDTA G FD&C Yellow No. 5 G FD&C RedNo. 4 G EXT D&C Violet No. 2

EXAMPLE 2

[0034] This example illustrates the antipruritic effect of vitamin D₃formulated in corn oil for alleviating the pruritus of sunburn.

[0035] A corn oil solution of vitamin D₃ was prepared by adding 1 gramof vitamin D₃ to 20 ml corn oil with mixing for approximately 1 hourfollowed by brief heating to approximately 45° C. until dissolved. Oneml of this solution was mixed with 47 ml corn oil and 2 ml isopropylmyristate to obtain a final concentration of vitamin D₃ of 1000 μg/ml.

[0036] Subject CS developed a sunburn on the back and experienced severepruritus. Application of Vita Moist Cream provided some but incompleterelief. An intense pruritus returned and was then dealt by applying 1000μg/ml in corn oil with the result that the prutitus was immediately andcompletely alleviated. Approximately an one and one-half hours later,the pruritus returned and was alleviated by multiple applications ofVita Moist Cream, vitamin D₃ at 1000 μg/ml in corn oil, and constantmassaging. The pruritus abated completely about one-half hour afterthese applications.

EXAMPLE 3

[0037] This example illustrates the antipruritic effect of vitamin D₃formulated in water-based emulsions in alleviating the pruritus causedby poison ivy.

[0038] Water-based emulsion formulations:

[0039] Water-based emulsions were prepared using Keri® lotion(Bristol-Meyers Squibb Co., N.Y.) and Eucerin® lotion (Beiersdorf, Inc.,Norwalk, Conn.).

[0040] Keri® lotion has the following composition as indicated on thecontainer label.

KERI® LOTION

[0041] Water

[0042] Petroleum

[0043] Glycerin

[0044] Dimethicone

[0045] Steareth-2

[0046] Cetyl Alcohol

[0047] Benzyl Alcohol

[0048] Laureth-23

[0049] Magnesium Alimunim Silicate

[0050] Tocopheryl Linoleate

[0051] Carbomer

[0052] BHT

[0053] Sodium Hydroxide

[0054] Disodium EDTA

[0055] Quaternium-16

[0056] Eucerin® lotion has the following composition as indicated on thecontainer label.

EUCERIN® LOTION

[0057] Water

[0058] Mineral Oil

[0059] Isopropyl Myristate

[0060] PEG-40 Sorbitan

[0061] Peroleate

[0062] Glyceryl Lanolate

[0063] Sorbitol

[0064] Propylene Glycol

[0065] Cetyl Palmitate

[0066] Magnesium Sulfate

[0067] Aluminum Sterate

[0068] Lanolin

[0069] Alcohol

[0070] BHT

[0071] Methylchloroisothiazolinone

[0072] Methylisothiazolinone

[0073] Keri® lotion preparations were made containing variousconcentrations of vitamin D₃ by mixing stock solutions as indicatedbelow and heating the mixture at 46-50° C. with occasional stirring. 869μg/ml: One ml of the 5% solution of vitamin D₃ from example 2 was mixedwith 2 ml corn oil to obtain 16,666 μg/ml solution. 0.55 ml of thissolution was then mixed with ten ml of Keri® lotion. 521 μg/ml: 0.55 mlof vitamin D₃ in corn oil at 10,000 μg/ml as described above was addedto 10 ml Keri® Lotion. 502 μg/ml: 0.55 ml of the 10,000 solution of wasmixed with 10 ml Keri® Lotion and 0.4 ml isopropyl myristate. 52 μg/ml:0.55 ml of 1,000 μg/ml stock solution, prepared by mixing 1 ml of 5%vitamin D₃ stock with 2 ml isopropyl myristate and 47 ml corn oil, wasadded to 10 ml Keri® Lotion. 10 μg/ml: 0.55 ml of 200 μg/ml stocksolution, prepared by mixing 1 ml of 5% vitamin D₃ stock with 49 ml cornoil and subsequently diluted 1:5 in corn oil, was added to 0.4 mlisopropyl myristate and 10 ml Keri® Lotion.

[0074] Eucerin® lotion preparation at 869 μg/ml was made as describedabove for Keri® lotion.

[0075] Vita Moist Cream had the composition as shown in example 1.

[0076] As placebo control Care Deeply Hand and Nail Cream (Avon, N.Y.)hereinafter referenced as Care Deeply, has the following composition:

CARE DEEPLY HAND AND NAIL CREAM

[0077] Purified Water

[0078] Glycerin

[0079] Cocoa Butter

[0080] Cetearyl Alcohol

[0081] Isopropyl Myristate

[0082] Emulsifying Wax

[0083] Ceteareth-20

[0084] Isopropyl Lanolate

[0085] Choleth-24

[0086] Glycol Stearate

[0087] Methylparaben

[0088] Lanolin Oil

[0089] Imidazolidinyl Urea

[0090] Carbomer-941

[0091] Dimethicone

[0092] Magnesium Aluminum Silicate

[0093] Triethanolamine

[0094] Fragrance

[0095] Tetrasodium EDTA

[0096] FD&C Yellow No. 5

[0097] FD&C Red No. 4

[0098] FD&C Blue No. 1

[0099] Testing Procedure: Subject MS contracted poison ivy rash andtested the various preparations above. Preparations were evaluated bythe subject after application to an area of rash approximately 1-10square centimeters. Comparisons were made of antipruritic effect bymarking on a 100 mm visual analog scale consisting of a plain line withthe left end labeled “None” and the right end labeled “Maximal”. Thesubject was instructed to mark the scale at a point which she feltcorresponded to the level of itchiness that she was feeling at thetreatment site at the appropriate time. The samples were coded so thatthe subject was not aware of what a given sample was and she was nottold if they were expected to have an effect. She carried out theevaluation unaided, applying the samples in any order she chose exceptwhere side-by-side comparisons were made as indicated in the tables.From the marked scale the pruritic score was determined as the number ofmm from the left side of the scale to the subject's mark. Thus a highervalue indicates a high level or pruritus and a low value indicates a lowlevel to no pruritus. Tables 1a through 1c show the antipruritic effectof water-based emulsion preparations.

[0100] Table 1a shows an antipruritic effect of Vita Moist Creamcontaining vitamin D₃ at 10 μg/ml compared to the control cream, CareDeeply. The pruritus was completely alleviated one minute afterapplication. TABLE 1a VITA MOIST (Vitamin D₃- 10 μg/ml)* Time CareDeeply Vita Moist (min) Control (D₃ - 10 μg/ml) 0 81 81  1 75 0 5 74 010  76 0

[0101] In Table 1b, it is seen that Keri® lotion as a vehicle forvitamin D₃ also produces a rapid and complete antipruritic effect as wasseen in Table 1a for Vita Moist Cream. Also, it is seen that theaddition of isopropyl myristate to the formulation did not effect theantipruritic effect of vitamin D₃. TABLE 1b KERI LOTION (containingVitamin D₃) Time (min) 10 10 10* 10* Mean 0 80  77  78  80  79  1 1 0 00 0 5 0 0 0 0 0 10  0 0 0 0 0

[0102] Table 1c shows that concentrations of vitamin D₃ from 10 through869 μg/ml are effective in rapidly and effectively relieving pruritus.TABLE 1c KERI LOTION (with added Isopropyl Myristate) Time Vitamin D₃Concentrations (min) 0 10** 52 502 521* 869 0 82 79  77  80  80  82  166 0 35  0 81  0 5 47 0 0 0 0 0 10  25 0 0 0 0 0

[0103] The formulation of 869 μg/ml vitamin D₃ in Eucerin® was comparedwith a Eucerin® control vehicle prepared from Eucerin® with an addedamount of corn oil identical to that in the active formulation butcontaining no vitamin D₃. No scores were recorded, however, the subjectindicated that the Eucerin®-vitamin D₃ preparation stopped the pruritusinstantly and completely whereas the control had no antiprutitic effect.

EXAMPLE 4

[0104] This example illustrates the antipruritic effect of vitamin D₃formulated in oil-based preparations in alleviating the pruritus causedby poison ivy.

[0105] A petroleum jelly formulation was prepared as follows. One gramof vitamin D₃ was dissolved in 20 ml corn oil as described in example 2.One ml of the resultant 5% solution was mixed with 4 ml corn oil toobtain a 10,000 μg/ml solution. Ten ml of petroleum jelly was then mixedwith 0.55 ml of the 10,000 μg/ml solution upon heating to 50-55° C. togive a resultant concentration of 521 μg/ml. Placebo control was made byadding 0.55 ml corn oil to 10 ml petroleum jelly.

[0106] The corn oil formulation was prepared by adding 1 ml of the 5%stock solution of vitamin D₃ in 2 ml isopropyl myristate and 47 ml cornoil to give a final concentration of 1000 μg/ml.

[0107] Vitamin A and D Ointment (Schering-Plough, Memphis, Tenn.)contained the label-indicated ingredients of vitamin A at 1856 I.U./gand vitamin D at 270 I.U./g or 6.75 μg/ml in white petrolatum and zincoxide.

[0108] The patient and test procedures were as described in example 3.The results of tests using oil-based formulations are in tables 2athrough 2c.

[0109] In Table 2a it is seen that corn oil as a vehicle for vitamin D₃at 1000 μg/ml produced no detectable antipruritic effect when the meanof two tests were compared to vehicle control. In contrast, Table 2bshowed an antipruritic effect for vitamin D₃ at a concentration of 521μg/ml in the vehicle, petroleum jelly. The commercial product, A and Dointment shown in Table 2c showed no antipruritic effect. TABLE 2a CORNOIL Vitamin D₃ Time Control (1000 μg/ml) (min) 1 2 Mean 1 2 Mean 0 82 8282 80 81 81 1 81 48 65 80 81 81 5 81 12 47 81 58 70 10  83  2 43 60 5859

[0110] TABLE 2b PETROLEUM JELLY Time Vitamin D₃ (min) Control (521μg/ml) 0 80 72 1 79 11 5 78 10 10  58  9

[0111] TABLE 2c A AND D OINTMENT* A and D Petroleum Ointment Time Jelly(D₃-6.75 μg/ml) (min) 1 2 Mean 1 2 Mean 0 81 68 75 81 58 70 1 81 2 42 161 31 5 0 0 0 80 61 71 10  0 43 22 82 52 67

EXAMPLE 5

[0112] This example illustrates the antipruritic effect of vitamin D₃formulated in a water-based suspension in alleviating the prurituscaused by poison ivy.

[0113] Vita Moist Cream was used as control reference formulation andthis had the composition as shown in example 1. Vita Moist Body Lotion(Avon, N.Y.), is a commercially available aqueous suspension formulationcontaining vitamin D₃. This composition contains the followingingredients. VITA MOIST BODY LOTION A Purified Water E Stearic Acid EHydrogenated Soybean Oil E Glycerin E Squalane F Cetyl Acetate FTriethanolamine F Glyceryl Stearate F Sesame Oil F Methylparaben FMagnesium Aluminum Silicate F Fragrance F Propylparaben F AcetylatedLanolin Alcohol .05000 Tocopheryl Acetate .02500 Retinyl Palmitate FCorn Oil F BHT F Propylene Glycol F SD Alcohol 40-B .00125Cholecalciferol F BHA F Disodium EDTA F FD&C Yellow No. 5 F FD&C Red No.4 F EXT D&C Violet No. 2

[0114] The patient and test procedures were as described in example 3.The results of tests using oil-based formulations are in Table 3. TABLE3 VITAMIN D³ SUSPENSION (VITA MOIST LOTION) Vita Moist Cream Vita MoistLotion Time (D³ - 10 μg/ml) (D₃ - 12.5 μg/ml) (min) 1 2 Mean 1 2 Mean 070  79  74  71  78 74 1 0 78  39  49  78 64 5 0 0 0 11  56 34 10  0 0 03  5  4

[0115] As reported in example 3, Vita Moist Cream again completelyalleviated the pruritus, although in this test, complete effectivenesswas seen at the 5 minute observation rather than at the 1 minuteobservation in example 3. In comparison to this, Vita Moist Lotion onlypartially alleviation of the pruritis at 5 minutes and nearly completerelief was obtained by 10 minutes. Thus the suspension preparationappeared to be less rapid in producing the antipruritic effect than wasthe emulsion preparation, Vita Moist Cream.

EXAMPLE 6

[0116] This example illustrates the dose-response relationship ofVitamin D₃ in a water-based emulsion vehicle prepared by mixing VitaMoist Cream containing Vitamin D₃ with Care Deeply Cream which containsno Vitamin D₃.

[0117] Serial dilutions of Vita Moist Cream were made from an initial 5ml quantity of Vita Moist Cream by adding successive 5 ml quantities ofthe diluent, Care Deeply Cream, to the starting formulation andsubsequent 5 ml aliquots of successive dilutions as follows:

[0118] 1.5 ml Vita Moist+5 ml diluent - - - 5.0 μg/ml

[0119] 2.5 ml of 5 μg/ml+5 ml diluent - - - 2.5 μg/ml

[0120] 3.5 ml of 2.5 μg/ml+5 ml diluent-1.25 μg/ml

[0121] 4. 5 ml of 1.2 μg/ml+5 ml diluent-0.5 μg/ml

[0122] 5.5 ml of 0.5 μg/ml+5 ml diluent-0.25 μg/ml

[0123] 6. 5 ml diluent

[0124] After coding with numbers 1-6 as above, the preparations wererandomly sorted and again coded A-E and tested two at a time inalphabetical order. The results are shown in the figure. As can be seenconcentrations of 2.5 and 5 μg/ml produced rapid and completealleviation of pruritus. The concentrations of 1.25 μg/ml and 0.5 μg/mlproduced some antipruritic effect but the effect was not complete norwas it rapid and sustained. The minimal effective concentration in thisformulation appears to be between 1.25 and 2.5 μg/ml.

EXAMPLE 7

[0125] The following example illustrates the clinical testing of vitaminD formulations in patients having uremic pruritus.

[0126] In this study, vitamin D formulations will be tested againstplacebo. The vitamin D preparations will be based upon the formulationsdiscussed above. The placebo will contain only the formulation withoutvitamin D.

[0127] The study would be double blind, meaning that both the nurse andthe patient will be unaware of which cream contains the test materialand which contains only placebo. The containers will be coded so thatonly the attending physician will know which is which. The code may bedifferent from one formulation set to the next.

[0128] The nurse protecol is as follows:

[0129] The patient must be suffering from chronic kidney failure and beexperiencing bothersome itchiness at the time of the office visit. Thepatient will be asked if they would like to volunteer to try this newtreatment. It will be explained that this is a trial of a cream thatrelieves itchiness in chickenpox and poison ivy and that it may or maynot help them.

[0130] The patient will be assisted in understanding and completing thequestionnaire. If needed, the nurse can assist by writing the answersgiven by the patient. The questionnaire is as follows: Cream Number _(—)_(—)  1. Patient's name and phone number.  2. Date and time.  3.Age/Sex.  4. Date when dialysis was started.  5. What kind of renaldisease do you have?  6. Do you have a history of persistent itchiness?If so, for how long?  7. Is your itchiness constant or does it come andgo? If it's not constant, when is it usually the worst?  8. Are youitching right now?  9. Do you have itchiness all over your body or onlyon part of your body? If only on part of your body, please indicatewhere. 10. What treatments have you tried to reduce the itchiness andwhich have been the most effective? Nurses' comments (to be filled outafter evaluation): Follow up comments: Nurses' signature Doctors'signature

[0131] Chose the sites to apply the creams based on where the itching ismost severe. Apply creams “X” and “O” to areas of roughly equal size anditchiness. Indicate under “Nurses' comments” where the creams wereapplied. If the itching is general, use one forearm for the test creamand the other forearm for the placebo cream. The cream should soak incompletely. If it doesn't, you put too much on. If the patient has anadverse reaction to the cream, stop the trial and remove the creamimmediately.

[0132] If one of the creams relieves the itching, let them apply thecream to all of the affected areas of skin after the trial is completedbefore leaving the office. Ask the patient to make a note of when theitchiness returns and explain that you will make a follow up call to askhow long the treatment lasted. Do not give any extra to take home.Explain that the attending physician is barred by law to prescribe ordispense it.

[0133] Please indicate under “Nurses' comments” if there is anythingabout the patient that you think we should know when reviewing thequestionnaire. This could include problems other than uremia that couldcause pruritus.

[0134] Treatment is evaluated by the patient as discussed in Example 3above. The patient is instructed as to how to mark the 100 mm visualscale from “None” to “Maximal” pruritus. The scale is explained with nosuggestion as to where the mark should be placed. Only the patient willdecide where to place the mark. Patient's name and date: TREATMENTEVALUATION Please indicate how serious the itchiness is using thefollowing scales. make a mark on the line at the point that you feelcorresponds to the severity of the itchiness that you are experiencingat the treatment sites for each appropriate time. Slight itchiness wouldbe indicated by making a mark near the left side of the scale whilesevere itchiness would be indicated by making a mark near the right sideof the scale. Maximal itchiness means the most severe itchiness that youcan imagine. BEFORE APPLICATION Site X NONE MAXIMAL Site O NONE MAXIMALONE MINUTE AFTER APPLICATION Site X NONE MAXIMAL Site O NONE MAXIMALFIVE MINUTES AFTER APPLICATION Site X NONE MAXIMAL Site O NONE MAXIMALTEN MINUTES AFTER APPLICATION Site X NONE MAXIMAL Site O NONE MAXIMALPlease describe in your own words the effect of the cream on theitchiness. If this treatment is effective, we will call you for a followup assessment to find out how long the treatment is effective. Pleasetry to note when the itchiness returns. Thank you very much!

[0135] Approximately 10 patients will be used in the study and eachpatient will receive both vitamin D treatment formulation and placebo.Data will be collected and statistical comparison will be made betweeneffects of the formulation and effects of placebo.

[0136] In view of the above, it will be seen that the several advantagesof the invention are achieved and other advantageous results attained.

[0137] As various changes could be made in the above methods andcompositions without departing from the scope of the invention, it isintended that all matter contained in the above description and shown inthe accompanying drawings shall be interpreted as illustrative and notin a limiting sense.

What is claimed is:
 1. A method for treating pruritus comprisingtopically administering vitamin D or an analog thereof in atherapeutically effective formulation which is pharmaceuticallyacceptable for topical application.
 2. The method according to claim 1wherein the therapeutically effective formulation is an emulsioncomprising water, a water-insoluble organic liquid, a surface activeagent, and vitamin D or an analog thereof.
 3. The method according toclaim 2 wherein the vitamin D comprises a compound selected from thegroup consisting of alacalcidol, calcifediol, calcitriol,cholecalciferol, dihydrotachysterol and ergocalciferol.
 4. The methodaccording to claim 2 wherein the analog of vitamin D comprises a vitaminD compound having side-chain modifications of introduction ofunsaturation; transposing, adding, removing or substituting hydroxylgroups; substituting hydrogens; forming carbocyclic structure;introducing a heteroatom link; inverting stereochemically; removing oradding alkyl groups; or changing the number of links in the side chain.5. The method according to claim 2 wherein the surface active agent isselected from the group consisting of PEG-40 stearate, steareth-2,PEG-40 sorbitan peroleate, laureth-23 and combinations thereof.
 6. Themethod according to claim 5 wherein the therapeutically effectiveformulation comprises at least about 50% water, from about 1 to about 5%PEG-40 stearate, from 1 to about 5% steareth-2 and cholecalciferol at aconcentration of about 10 μg/ml.
 7. The method according to claim 6wherein the therapeutically effective formulation comprisescholecalciferol at a concentration of at least about about 2.5 μg/ml. 8.The method according to claim 7 wherein the pruritus results from acondition selected from the group consisting of chickenpox, shingles,plant toxins such as poison ivy, insect bites, chronic kidney failure,liver diseases such as primary biliary cirrhosis and alcoholiccirrhosis, malabsorption syndromes such as steatorhea, HIV infection,AIDS related eosinophilic pustular folliculitus, psoriasis, atopicdermatitis, photosensitivity disorders, lichen planus, polycythemiavera, Grover's disease, glanuloma annulare, lichen nitidus, prurigonodularis, macular amyloidosis, urticaria pigmentosa, aquagenicpruritus, pemphigus vulgarus, lupis vulgaris, healing cuts and burns,senile pruritus, hypereosinophilic syndrome, chronic uticaria, pruriticeye conditions, stress, and combinations thereof.
 9. The methodaccording to claim 1 wherein the therapeutically effective formulationcomprises vitamin D or analog thereof and a water insoluble organicliquid.
 10. The method according to claim 9 wherein the vitamin Dcomprises a compound selected from the group consisting of alacalcidol,calcifediol, calcitriol, cholecalciferol, dihydrotachysterol andergocalciferol.
 11. The method according to claim 9 wherein the analogof vitamin D comprises a vitamin D compound having side-chainmodifications of introduction of unsaturation; transposing, adding,removing or substituting hydroxyl groups; substituting hydrogens;forming carbocyclic structure; introducing a heteroatom link; invertingstereochemically; removing or adding alkyl groups; or changing thenumber of links in the side chain.
 12. The method according to claim 10wherein the water-insoluble organic liquid is selected from the groupconsisting of corn oil, petroleum jelly and fish oil.
 13. The methodaccording to claim 12 wherein the therapeutically effective formulationcontains at least about 521 μg cholecalciferol per ml.
 14. The methodaccording to claim 13 wherein the pruritus results from a conditionselected from the group consisting of chickenpox, shingles, plant toxinssuch as poison ivy, insect bites, chronic kidney failure, liver diseasessuch as primary biliary cirrhosis and alcoholic cirrhosis, malabsorptionsyndromes such as steatorhea, HIV infection, AIDS related eosinophilicpustular folliculitus, psoriasis, atopic dermatitis, photosensitivitydisorders, lichen planus, polycythemia vera, Grover's disease, glanulomaannulare, lichen nitidus, prurigo nodularis, macular amyloidosis,urticaria pigmentosa, aquagenic pruritus, pemphigus vulgarus, lupisvulgaris, healing cuts and burns, senile pruritus, hypereosinophilicsyndrome, chronic uticaria, pruritic eye conditions, stress, andcombinations thereof.
 15. The method according to claim 1 wherein thetherapeutically effective formulation is a suspension comprising waterand a dispersed phase containing vitamin D or analog thereof.
 16. Themethod according to claim 15 wherein the vitamin D comprises a compoundselected from the group consisting of alacalcidol, calcifediol,calcitriol, cholecalciferol, dihydrotachysterol and ergocalciferol. 17.The method according to claim 15 wherein the analog of vitamin Dcomprises a vitamin D compound having side-chain modifications ofintroduction of unsaturation; transposing, adding, removing orsubstituting hydroxyl groups; substituting hydrogens; formingcarbocyclic structure; introducing a heteroatom link; invertingstereochemically; removing or adding alkyl groups; or changing thenumber of links in the side chain.
 18. The method according to claim 16wherein the dispersed phase comprises stearic acid and hydrogenatedsoybean oil and squalene.
 19. The method according to claim 18 whereinthe therapeutically effective formulation contains at least about 10 μgcholcalciferol per ml.
 20. The method according to claim 19 wherein thepruritus results from a condition selected from the group consisting ofchickenpox, shingles, plant toxins such as poison ivy, insect bites,chronic kidney failure, liver diseases such as primary biliary cirrhosisand alcoholic cirrhosis, malabsorption syndromes such as steatorhea, HIVinfection, AIDS related eosinophilic pustular folliculitus, psoriasis,atopic dermatitis, photosensitivity disorders, lichen planus,polycythemia vera, Grover's disease, glanuloma annulare, lichen nitidus,prurigo nodularis, macular amyloidosis, urticaria pigmentosa, aquagenicpruritus, pemphigus vulgarus, lupis vulgaris, healing cuts and burns,senile pruritus, hypereosinophilic syndrome, chronic uticaria, pruriticeye conditions, stress, and combinations thereof.